Gastroenteropancreatic (GEP) neuroendocrine neoplasm (GEP-NEN), also referred to as Gastroenteropancreatic Neuroendocrine Tumor and Neuroendocrine Tumor (NET), is the second most prevalent malignant tumor in the gastrointestinal (GI) tract in the U.S. Incidence and prevalence have increased between 100 and 600 percent in the U.S. over the last thirty years, with no significant increase in survival.
Heterogeneity and complexity of GEP-NENs has made diagnosis, treatment, and classification difficult. These neoplasms lack several mutations commonly associated with other cancers and microsatellite instability is largely absent. See Tannapfel A, Vomschloss S, Karhoff D, et al., “BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors,” Am J Clin Pathol 2005; 123(2):256-60; Banck M, Kanwar R, Kulkarni A A, et al., “The genomic landscape of small intestine neuroendocrine tumors,” J Clin Invest 2013; 123(6):2502-8; Zikusoka M N, Kidd M, Eick G, et al., Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 2005; 104:2292-309; Kidd M, Eick G, Shapiro M D, et al. Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors,” Cancer 2005; 103(2):229-36.
Individual histopathologic subtypes as determined from tissue resources e.g., biopsy, associate with distinct clinical behavior, yet there is no definitive, generally accepted pathologic classification or prediction scheme, hindering treatment assessment and follow-up.
Existing diagnostic and prognostic approaches for GEP-NENs include imaging (e.g., CT or MRI), histology, measurements of circulating hormones and proteins associated with NENs e.g., chromogranin A and detection of some gene products. Available methods are limited, for example, by low sensitivity and/or specificity, inability to detect early-stage disease, or exposure to radiation risk. GEP-NENs often go undiagnosed until they are metastatic and often untreatable. In addition, follow-up is difficult, particularly in patients with residual disease burden.
There is a need for specific and sensitive methods and agents for the detection of GEP-NEN, including stable and progressive GEP-NEN, for example, for use in diagnosis, prognosis, prediction, staging, classification, treatment, monitoring, and risk assessment, and for investigating and understanding molecular factors of pathogenesis, malignancy, and aggressiveness of this disease. For example, such methods and agents are needed that can be repeatedly and directly collected with low risk exposure e.g., non-invasive peripheral blood test, be performed simply, rapidly, and at relatively low cost.
The present application overcomes the above-noted problems by providing novel compositions, methods, and kits for accurately diagnosing, detecting, and monitoring the presence of GEP-NENs and/or the types or stage of GEP-NEN in circulating peripheral blood samples. The described embodiments furthermore may be used to identify a level of risk for a patient to develop a progressive GEP-NEN, and/or to determine the risk of residual or reoccurring progressive GEP-NEN in a post-surgery or post-somatostatin treated human patient. In addition, it can be used as a prognostic for predicting response to therapy e.g., peptide receptor radiotherapy (PRRT).